The present invention is directed to antigen-binding polypeptides which specifically bind the LIGHT polypeptide, and methods of making and using such antibodies. Specifically the invention is directed to humanized antigen-binding polypeptides which specifically bind the LIGHT polypeptide. The antigen-binding polypeptides are useful in treating and diagnosing immune, inflammatory and malignant diseases and conditions such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, rheumatoid arthritis and transplantation.
Proteins that are structurally related to tumor necrosis factor (TNF) are collectively referred to as the TNF super family. LIGHT, a TNF super family member, is expressed on activated T-cells and immature dendritic cells (Tamada et al., J. Immunology. 2000). LIGHT is a type II transmembrane protein and has been designated as TNF superfamily member 14 (TNFSF14) and is also called TL5, LTg, CD258 and HVEML. LIGHT is a T costimulatory molecule and induces T-cell proliferation and cytokine production (Tamada K. et al., Nat. Med. 2000). LIGHT also induces an inflammatory response in monocytes and endothelial cells (Otterdal et al., Blood 2006; Chang et al., J. Biomed. Sci. 2005).
LIGHT binds to 3 distinct receptors expressed on different cell types: herpes virus entry mediator (HVEM) expressed on T-cells and B cells (Kwon et al., J. Biol. Chem 1997)), lymphotoxin β receptor (LTβR) expressed on stromal cells and non-hematopoietic cells (Ettinger et al., Curr Top Microbiol Immunol. 2000) and decoy receptor 3/TR6. LIGHT on both dendridic cells and T-cells augments T-cell proliferation and cytokine production. rLIGHT can directly costimulate T-cell responses (Tamada K. et al., Nat. Med. 2000).
The role of LIGHT in various inflammatory and disease conditions has been demonstrated by various models using LIGHT deficient models and LIGHT overexpressing transgenic animals. Over expression of LIGHT in mice results in a hyper activated peripheral T-cell population and spontaneous development of severe autoimmune disease. (Wang et al., Clin. Invest. 2001). Targeted disruption of LIGHT causes a defect in co-stimulatory activation of T-cells and Th1 type immune response. (Scheu et al., J. Exp. Med. 2002; Xu et al. J Immunol. 2007).
Because of its potent stimulatory activity on T-cells, LIGHT is an important component of chronic inflammation. Thus, antibodies to LIGHT, in particular LIGHT antagonist antibodies, would be useful in treating diseases associated with chronic inflammation. Such disease include, but are not limited to those discussed below.
Dysregulated immune response to gut flora is the main cause of inflammatory bowel disease (IBD). T helper cells play an essential role in the aberrant immune repose in IBD. In particular, Th1 cells have been linked to Crohn's disease. The critical role of LIGHT in intestinal inflammation has been demonstrated by several studies. LIGHT over-expressing transgenic mice are susceptible to T-cell mediated autoimmune diseases and LIGHT transgenic mice exhibit severe T-cell mediated intestinal inflammation and develop colitis (Wang J. et al., J. Clin. Invest. 2004; Wang J. et al., J. Immunol 2005; Wang et al., J. Clin. Invest 2001; Shaikh et al., J. Immunol. 2001). Additionally, blocking the interaction of LIGHT to its receptor by soluble LTβR-Fc ameliorates TNBS-induced colitis (An, M M et al., Pharmacol. Res. 2005). LIGHT maps to the region overlapping a susceptibility locus for IBD on human chromosome 19p13.312-14 (Rioux et al., Am. Hum. Genet. (2000); Bonen et al., Gastroenterology (2003)).
High levels of LIGHT protein have been detected in the synovial fluid of patients with rheumatoid arthritis (RA). See for example, Recombinant LIGHT-induced inflammatory mediators in synovial fibroblasts from RA patients (Pierer et al., Rheumatology (2007); Kang et al., Arthritis & Rheumatism (2007)) and Blocking LIGHT-receptor interaction prevents development of Collagen-Induced Arthritis (Fava et al., J. Immunol. (2003)). Finally, in November 2007, Biogen IDEC announced the use of baminercept (LTβR-Fc fusion protein) in Phase IIa clinical trials for RA patients (Biogen IDEC Press Release dated Nov. 9, 2007).
LIGHT is upregulated in experimental models of hepatitis. Blocking interaction of LIGHT with LIGHT receptors, by treatment with antibody or soluble LTβR, significantly attenuated hepatic inflammation and reduced the production of inflammatory cytokines and protected mice from lethal hepatitis (Anand et al., J. Clin. Invest. (2006); An et al. Biol. Pharm. Bull. (2006)).
Several studies have demonstrated that blockade of LIGHT-receptor interaction prevents graft-versus-host disease (GVHD) and prolongs allograft survival in animal models (Xu et al., Blood (2007); Ye et al., J. Exp. Med. (2002); Fan et al., Transplantation (2007)).
In addition to the studies mentioned above, blocking of LIGHT receptors (LTβR and HVEM) dramatically reduce signs of disease in different animal models such as Collagen-Induced Arthritis (CIA) and Experimental Autoimmune Encephalomyelitis (EAE), which is an animal model for multiple sclerosis (MS) (Fava et al., J Immunol. (2003) and Suen et al., J. Exp. Med. (1997)). LIGHT knockout mice are also deficient in production of IL-12 and, as a result, lack the ability to develop IFNγ mediated, antigen specific Th1 responses to inflammatory stimuli.
Thus, there is a need in the art to create antigen-binding polypeptides and antagonist antigen-binding polypeptides which specifically bind to LIGHT to treat inflammatory, malignant and autoimmune diseases and conditions such as multiple-sclerosis, IBD and RA as well as other disease described above or known in the art. Antigen-binding polypeptides and antagonist antigen-binding polypeptides which specifically bind LIGHT have a number of advantages compared to the use of a soluble receptor such as: 1) antibodies have a longer half-life in the bloodstream compared to Fc-fusion proteins; 2) antibodies have higher efficacy as the antibody can be designed to have a higher affinity for LIGHT compared to soluble receptors; and 3) antibodies are a safer alternative to soluble receptors because of the specificity to LIGHT. LIGHT antagonist antibodies would only block LIGHT mediated signaling, thus ameliorating the local inflammatory process without systemic depletion of the secondary lymphoid tissue architecture caused by soluble receptors which can eventually lead to immunosuppresion.